Intracellular receptors (IR) form a class of structurally related genetic regulators known as "ligand dependent transcription factors" (R. M. Evans, Science, 240, 889, 1988). The steroid receptor family is a subset of the IR family, including progesterone receptor (PR), estrogen receptor (ER), androgen receptor (AR), glucocorticoid receptor (GR), and mineralocorticoid receptor (MR).
The natural hormone, or ligand, for the PR is the steroid progesterone, but synthetic compounds, such as medroxyprogesterone acetate or levonorgestrel, have been made which also serve as ligands. Once a ligand is present in the fluid surrounding a cell, it passes through the membrane via passive diffusion, and binds to the IR to create a receptor/ligand complex. This complex then translocates to the nucleus of the cell where it binds to a specific gene or genes present in the cell's DNA. Once bound to a specific DNA sequence the complex modulates the production of the mRNA and protein encoded by that gene.
A compound that binds to an IR and mimics the action of the natural hormone is termed an agonist, whilst a compound which inhibits the effect of the hormone is an antagonist.
PR agonists (natural and synthetic) are known to play an important role in the health of women. PR agonists are used in birth control formulations, typically in the presence of an ER agonist. ER agonists are used to treat the symptoms of menopause, but have been associated with a proliferative effect on the uterus (in non-hysterectomized women) which can lead to an increased risk of uterine cancers. Co-administration of a PR agonist reduces or ablates that risk.
PR antagonists may also be used in contraception. In this context they may be administered alone (Ulmann, et al, Ann. N. Y. Acad. Sci., 261, 248, 1995), in combination with a PR agonist (Kekkonen, et al, Fertility and Sterility, 60, 610, 1993) or in combination with a partial ER antagonist such as tamoxifen (WO 96/19997 A1 Jul. 4, 1996).
PR antagonists may also be useful for the treatment of hormone dependent breast cancers (Horwitz, et al, Horm. Cancer, 283, pub: Birkhaeuser, Boston, Mass., ed. Vedeckis) as well as uterine and ovarian cancers. PR antagonists may also be useful for the treatment of non-malignant chronic conditions such as fibroids (Murphy, et al, J. Clin. Endo. Metab., 76, 513, 1993) and endometriosis (Kettel, et al, Fertility and Sterility, 56, 402, 1991).
PR antagonists may also be useful in hormone replacement therapy for post-menopausal patients in combination with a partial ER antagonist such as tamoxifen (U.S. Pat. No. 5,719,136). PR antagonists such as Mifepristone have also been shown to have bone sparing effects in rodents, and as such may be useful in the treatment of osteoporosis associated with the menopause (Barengolts, et al, Bone, 17, 21, 1995).
PR antagonists, such as mifepristone and onapristone, have been shown to be effective in a model of hormone dependent prostate cancer, which may indicate their utility in the treatment of this condition in men (Michna, et al, Ann. N..Y. Acad. Sci., 761, 224, 1995).
Jones, et al, (U.S. Pat. No. 5,688,810) described the PR antagonist dihydroquinoline 1. ##STR2##
Jones, et al, described the enol ether 2 (U.S. Pat. No. 5,693,646) as a PR ligand. ##STR3##
Jones, et al, described compound 3 (U.S. Pat. No. 5,696,127) as a PR ligand. ##STR4##
Zhi, et al, described lactones 4, 5 and 6 as PR antagonists (J. Med. Chem., 41, 291, 1998). ##STR5##
Zhi, et al, described the ether 7 as a PR antagonist (J. Med. Chem., 41, 291, 1998). ##STR6##
Combs, et al., disclosed the amide 8 as a ligand for the PR (J. Med. Chem., 38, 4880, 1995). ##STR7##
Perlman, et. al., described the vitamin D analog 9 as a PR ligand (Tet. Letters, 35, 2295, 1994). ##STR8##
Hamann, et al, described the PR antagonist 10 (Ann. N.Y. Acad. Sci., 761,383, 1995). ##STR9##
Chen, et al, described the PR antagonist 11 (Chen, et al, POI-37, 16.sup.th Int. Cong. Het. Chem., Montana, 1997). ##STR10##
Kurihari, et. al., described the PR ligand 12 (J. Antibiotics, 50, 360, 1997). ##STR11##